We have initiated studies on the expression and regulation of receptors for human interferons (IFNs) on normal and malignant peripheral blood leukocytes. For these studies we radioiodinatd recombinant IFN-Alpha and IFN-Gamma by techniques which preserved the biological activity of the molecules. The binding of the iodinated IFNs to enriched and highly purified populations of peripheral blood cells from normal donors and from patients with lymphoproliferative diseases has been examined. We have observed that highly purified resting T lymphocytes and large granular lymphocytes from normal donors constitutively express receptors for IFN-Alpha and IFN-Gamma and we have measured the number of IFN receptors per cell and the affinities of the IFN-receptor interactions. The level of IFN receptor expression has varied with the activation state of the normal T lymphocytes. Proliferating normal lymphocytes express 3 to 5 fold more receptors for IFN Alpha than resting lymphocytes. In contrast the number of receptors for IFNGamma was transiently decreased by 10 fold by 18 hrs after activation of lymphocytes by lectins. We have observed that the cells from IFN-Alpha A responsive hairy cell leukemia patients expressed more IFN-Alpha A receptors than the cells from the nonresponsive chronic lymphocytic leukemia patients. However, due to difference in cell size, the receptor denisity on these two types of leukemic cells was similar. Taken together, our data suggest that although it may not be sufficient as a predictive paramater for clinical responsiveness to IFN, the absolute number of receptors per cell may be an important criterion in the antiproliferative response to IFN.